Periodic Reporting for period 4 - RECON (Reprogramming Conformation by Fluorination: Exploring New Areas of Chemical Space)
Período documentado: 2023-08-01 hasta 2024-07-31
Despite the abundance of organic compounds in Nature, only 12 contain fluorine. In contrast, fluorinated organic materials account for over 40% of all pharmaceuticals and agrochemicals. Closer inspection of the fluorination patterns in these functional molecules reveals striking extremes towards perfluorination (in both 2D and 3D scaffolds) or single site fluorination predominantly in aryl substituents. Consequently, most fluorinated moieties in functional materials lack stereochemical information and are thus achiral. This disparity between the paucity of naturally occurring organofluorine compounds and their venerable history in functional molecule design confirms the enormous potential of fluorinated materials in the discovery of novel properties. That progress has largely been confined to 3 dimensional achiral and 2 dimensional achiral architectures reflects the synthetic challenges associated with preparing stereochemical defined multiply fluorinated systems. A major limitation in the construction of C(sp3)-F units remains the need for substrate pre-functionalisation via oxidation and the competing substitution/elimination scenario that compromises efficiency in the deoxyfluorination. This problem is magnified in the synthesis of optically active fluorides where the deoxyfluorination can compromise the enantiopurity of the starting materials. The principle aim of RECON is to facilitate exploration of 3D, chiral space by providing access to multiply fluorinated, stereochemically complex organofluorine materials from simple feedstock using inexpensive, commercially available fluoride sources. In providing a modular platform to rationally place function on a structural basis, exploration of uncharted chemical space will accelerate the discovery of next generation materials for medicinal and agrochemistry, material sciences and bio-medicine.
During the initial funding period of this grant, emphasis effort has been heavily focussed on Work Package 1 (Efficient, Enantioselective, Catalytic Difluorination of Alkenes). Motivated by the potential of chiral resorcinol-based organocatalysts in oxidative fluorination processes, systematic structural investigations have been explored together with a studies on the impact of HF/amine ratios on the efficiency and selectivity of vicinal alkene difluorination. The catalysis-based synthesis of a chiral, pentafluorinated isopropyl group has been achieved that leverages (I)/I(III) catalysis (S. Meyer, J. Häfliger, M. Schäfer, J. J. Molloy, C. G. Daniliuc, and R. Gilmour, Angew. Chem. Int. Ed. 2021, 60, 6430-6434.). Inspired by the venerable history of chiral hybrid bioisosteres of short aliphatic groups in bioorganic chemistry, and the frequency with which the hexafluoroisopropyl group appears in medicinal and ago-chemistry, a chiral hybrid group in which the stereocentre contains the F, CH2F and CF3 groups would be valuable. Through an I(I)/I(III) catalysis strategy, it has been possible to achieve the direct vicinal fluorination of simple α-CF3-styrenes, thereby generating the target group. This novel scaffold displays intriguing conformational behaviour in which π→σ* and stereoelectronic gauche σ→σ * interactions lead to a high degree of pre-organization, and this has been fully interrogated by X-ray analyses. In the course of this funding period, preliminary validation of enantioselective catalysis has been achieved through a process of catalyst editing: this was a major focus. This transformation is remarkable and despite the intrinsic challenges of intermolecular fluorination, in which the significant steric and electronic barriers must be overcome, several enantioselective examples have been demonstrated. A chiral analogue of a TRPA1 antagonist from Hydra Biosciences has also been prepared to show the translational nature of the research. Modification of the substrate and tuning of the reaction conditions has allowed a second class of valuable pharmaceutical building blocks to be generated.
To obtain preliminary data for Work Package 4 (Application of Partially Fluorinated Chains in Bioisostere Design), a combined experimental and computational study into the effects of multiple H to F bioisosterism on molecular recognition in a model enzymatic reaction was performed. Single H to F replacements are common in drug discovery, and often result in advantageous changes in the physicochemical profile of small molecules. We explored the effect of a 1,3,5-trihalogen array on the desymmetrisation of a bis-acetate by the lipase from Pseudomonas fluorescens. Interestingly, fluorine conformational effects, such as the gauche effect (see Work Package 1), result in a reversed orientation of the bound substrate, giving rise to a change in the selectivity of enzyme function. A (bioisosteric) fluorine motif can be employed to invert the orientation of substrate binding, and that this substrate-control manifests itself in the formation of different, products resulting from the desymmetrisation at opposite ends of a meso chain (H versus F). The reaction is inhibited entirely when H is substituted by Cl. Given the rarity of organofluorine molecules in biology, and the increasing importance of saturated, C(sp3)-F containing scaffolds emergent in medicinal chemistry, a better understanding of molecular recognition in such systems is important. This study entitled „Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H → F Bioisosterism” has been published (Angew. Chem. Int. Ed. 2019, 58, 10990-10994) and led to an interdisciplinary investigation into bacterial imaging. “Enhancing Glycan Stability via Site-Selective Fluorination: Modulating Substrate Orientation by Molecular Design” (A. Axer, R. P. Jumde, S. Adam, A. Faust, M. Schäfers, M. Fobker, J. Koehnke, A. K. H. Hirsch and R. Gilmour, Chem. Sci. 2021, 12, 1286-1294). We discovered that site selective fluorination in a focussed group of maltotetraoses significantly increases the stability of model oligosaccharides by up to one order of magnitude. Modification at the monosaccharide furthest from the enzymatic cleavage termini leads to the greatest improvement in stability. In the case of α-amylase, docking studies indicate that this single point OH to F modification at the reducing end inverts the orientation in which the substrate is bound. This study has obvious clinical implications and was heavily inspired by the findings of the ERC Consolidator research.